Antipsychotics (Major tranquilizers or Neuroleptics)

1. Antipsychotics (Major tranquilizers orNeuroleptics) These drugs are useful in the treatment of psychoses especially schizophrenia, counteract or minimize hallucination and delusion Advantages • not affect consciousness or depress vital centers (contrary to the sedatives and hypnotics). • not induce psychological or physical dependence • over dosage is not fatal to adults. • have antiemetic and sympatholytic action. Mechanism of action It involves antagonism of brain dopamine receptors especially D2-type.

2. For atypical agents such as dibenzodiazepine (clozapine) and benzisoxazoles that have less EPS, they interact with dopamine D2-receptors and other receptors e.g acetylcholine, histamine and serotonin Side effects of neuroleptics • They can be attributed to their antagonistic activity to a variety of CNS receptors which include: 1-Blockade of adrenergic (a1/ a2) and histamine (H1) receptors: hypotension and sedation 2- Antagonismof muscarinic acetylcholine receptors (M1):They cause anticholinergic actions on cardiac, ophthalmic, GIT, bladder, and genital tissue.

3. 3- Antagonism of D2 receptors in nigrostriatal pathway: EPS. 4-Antagonism of D2-receptors in chemorecep tor trigger zone in the brain stem is responsible for their antiemetic effects e.g. promazine 5- Metabolic and endocrine side effects: weight gain, hyperprolactinemia and gynecomastia. 6- Potentiate the action of CNS depressants. 7- Other adverse reactions are jaundice, agranulocytosis and convulsions.

4. N.B. The anticholinergic action of atypical clozapine may be beneficial in negative symptoms of schizophrenia. Structural requirements for all neuroleptic drugs 1. A straight chain of three carbon atoms linking the basic ring nitrogen with a carbon, nitrogen, or oxygen atom.This atom may be a part ofbenzoyl group,phenothiazine or thioxanthene (tricyclic system). 2. A six-membered basic heterocyclic ring, such as piperazine or piperidine substituted in positions 1 and 4; the best substituents in position 4 are phenyl, anilino, methyl, or hydroxyethyl moieties. Y = C, N, O

5. Thus, all neuroleptics act at the molecular level via blockade of D2 receptors because they have these two features. • In complexation with dopamine receptors, "S-shaped" conformation of the four-atom sequence that links an aromatic ring to 3ry basic nitrogen in most neuroleptics may be involved. (a) (b) (c) The “S-shaped” conformation of piperidylidene thioxanthene (a) and diphenylbutylamines (b), has the same distance d as dopamine (c) molecule in its extended conformation.

6. Classification of antipsychotics I- Phenothiazine and thioxanthene derivatives. II- Butyrophenone and diphenylbutyl piperidine derivatives III - Benzamide derivatives IV- Benzazepine derivatives V- Indole derivatives. VI- Benzisoxazoles. VII- Antimanic agents. I- Phenothiazine and thioxanthene derivatives A) Phenothiazine derivatives They are characterized by a lipophilic fused tricyclic system linked via the nitrogen atom of the central ring through intermediate chain to a hydrophilic 3ry basic amine.

7. Interaction of phenothiazines and thioxanthenes with dopaminergic receptors Phenothiazines interact with the dopamine receptor at three sites A, B, and C to produce a response. The order of structural specificity at these sites is B > C > A. Site B (the intermediate chain) • Alkyl chain should contain 3 carbon atoms (n-propyl chain) which are optimal for activity. 2. If two carbons, it gives phenothiazines with either anticholinergic (ethopropazine) or antihistaminic (promethazine) activities without antipsychotic due to their isopropyl intermediate chain can not assume the preferred conformation. Proposed conformation in contact with the neuroleptic receptors X = Me promethazine X = Et Ethopropazine (Antiparkinsonian drug)

8. The R group located on the ß-carbon is important for structural specificity (certain degree of free rotation is necessary) due to it causes steric effects. a) If R = H , good neuroleptic potency is exhibited. b) If R = CH3, it enhances antihistaminic effects and decreases neuroleptic activity. c) If R = bulky group (phenyl or part of a ring), it decreases neuroleptic potency Site A (hydrophilic 3ry basic amine) 1- Site A is responsible for structural specificity due to molecule must enter into narrow slot. Thus, if two hydrogen atoms attached to the nitrogen are replaced: a) By methyl groups does not reduce the activity. b) By bulky alkyls decreaes activity (increased steric effect). 2- Replacement of the terminal dimethylamino group by piperazine or N-methylpiperazine group increases activity.

9. 3- Quaternary N atom at the side chain decrease lipid solubility and penetration into CNS and loss of activity. Site C (lipophilic phenothiazine nucleus): 1- The two flat aromatic rings are at right angles due to folding of phenothiazine nucleus. So, the R-2 substituent is too far from the receptor and not exerts any steric influence. 2- Substitution of ring H at 2-position only leads to increase activity; otherwise decreases potency. 3- The presence of an electron attracting but not ionizable gp at 2-position increase potency e.g. Cl (chloropromazine) and CF3 (trifluoropromazine). 4- Derivatives with 2-thioalkyl retain activity while the 2-OH derivatives are weakly active.

10. a) propylamines 5- In the preferred conformation of chlorpromazine, its side chain tilts toward the 2-chlorine-substituted ring due to attraction of the amine side-chain (protonated at physiologic pH) toward the ring containing the chlorine atom. • The electronegative chlorine atom is responsible for imparting asymmetryto chlorpromazine. • Phenothiazines and related compounds lacking a chlorine at 2-position are inactive as neuroleptic. Classification of Phenothiazines They are classified according to the hydrocarbon side chain into: • propylamines b) piperidines c) piperazines Promazine (Sparine) Chloropromazine 2-Chloro-10-[3-(dimethyl-amino)propyl]phenothiazine hydrochloride

11. a) Propylamines Chlorpromazine HCI (Largactil). • It is the prototype and used in the treatment of schizophrenia, control of acute psychosis and acute mania. • It is also used as antiemetic in postoperative nausea and vomiting. Assay: non-aqueous titration with 0.1 M perchloric acid. Synthesis: b) Piperidines Thioridazine HCl (Melleril). It has a relatively low EPS, low antiemetic activity but higher anticholinergic effect.

12. It is 10-[2-(1-Methyl-2-piperidyl)-ethyl] 2-(methylthio)phenothiazine c) Piperazine Trifluoperazine HCl (Stelazine). • It is 2-trifluoromethy-10-[3-(4-methy-1-piperazinyl)propyl]-phenothiazine • It is potent antipsychotic, with high EPS and low sedation and hypotensive effects. Fluphenazine decanoate (long acting) • The duration of action of fluphenazine with a free OH moiety can be prolonged by preparation of long chain fatty acid esters. • A single I.M. every 2-3 weeks with ester to avoid drug regimen and mal-absorption. Thioridazine HCl Trifluoperazine HCl

13. B) Thioxanthene derivatives (Modified phenothiazines) • Isosteric replacement of N atom of phenothiazine with sp2 carbon (methylidene) led to thioxanthenes. • Thioxanthenes are also nonpolar in which substituent at 2-position led to formation of either cis (Z) or trans (E) isomers. • Z isomer is more active than trans isomer or its saturated analogbecause it is superimposable on dopamine receptors. • Their pharmacological action and adverse effects are very similar to phenothiazine derivatives. Chlorprothixene (Taractan) • It is the biological isostere of chlorpromazine. • It is used in the treatment of schizophrenia. • It also has antihistaminic, antiemetic and hypotensive properties. Z-2-Chloro-9-(3-dimethyl aminopropylidine) thioxanthene

14. Metabolism of phenothiazine and thioxanthenes • The 7-hydroxylated phenothiazines as well as, the mono- and di-desmethylated products are active in vivo at dopamine D2 receptors, whereas the sulfoxide is inactive. • Most of the thioxanthenes do not form ring-hydroxylated derivatives. Thus, it can be concluded that in all tricyclic compounds, the structural features associated with high antipsychotic potency are: • A tricyclic ring with a six- or seven-membered central ring. • A side chain of 3 atoms between central ring and terminal NH2 group. • An electron-attracting group, such as chloro or trifluoromethyl, at 2- position of tricyclic ring.

15. II- Butyrophenone and diphenylbutyl piperidine derivatives a) Butyrophenone derivatives • In 1950, Janssen prepared propiophenone and butyrophenone analogs of meperidine in trial to increase the analgesic potency of meperidine. • The propiophenone analog had 200 times analgesic potency of meperidine but the butyrophenone analog displays activity resembling that of chlorpromazine but they are less toxic. Butyrophenone analog Meperidine Propiophenone analog

16. X = F or OCH3 Structure-activity Relationships All butyrophenones have the following general structure: 1) The potent compounds have p-fluorophenyl and the distance between its center and the 3ry nitrogen in the preferred conformation of haloperidol is 7.3 Å. 2) The attachment of 3ry amino group to the 4th carbon of the butyrophenone skeleton is essential for activity. 3) Lengthening, shortening, or branching decreases activity. 4) Replacement of keto moiety with thioketone or reduction of C=O group decreases neuroleptic potency. 5) the 3ry basic nitrogen is usually incorporated into six-membered ring (piperidine or piperazine) that is substituted in the para-position.

17. Haloperidol (Haldol) • It binds with high affinity to dopamine D2 and serotonin 5-HT2,receptors in brain. • It is used in the treatment of schizophrenia and acute psychosis. • It causes a high incidence of extrapyramidal reactions. Assay: non-aqueous titration with 0.05M perchloric acid. • Haloperidol decanoate is long-acting inj. (4-6 weeks). Droperidol • 1-{l-[3-(p-Fluorobenzoyl)propyl]- 1,2,3,6-tetrahydro-4-pyridyl}- 2-benzimidazolinone. 4-[4-(p-Chlorophenyl)-4-hydroxy) piperidino]-4-fluorobutyrophenone

18. It isa short-acting and used in anesthesia for its sedating and antiemetic effects in combination (Innovar) with fentanyl (narcotic analgesic). b) Diphenylbutyl piperidine neuroleptics • Modification or partial duplications of haloperidol by introducing 4-fluorophenyl moiety led to long acting derivatives such as pimozide and penfluridol (due to their high hydrophobic characters). • They are taken orally once a week in chronic schizophrenia. III- Benzamide derivatives • The o-methoxyprocainamide is a compound with local anesthetic properties and potent antiemetic action. • Further modification of the molecule yielded metoclopramide. pimozide

19. 1- Metoclopramide (Primperan, Plasil) • It possesses antiemetic activity (modifies gastric motility). • It was found to antagonize dopamine D2- receptors in the chemoreceptor trigger zone of the brain stem. 2- Pyrrolidinyl-containing benzamides a) Sulpiride (Dogmatil) • Sulpiride has little sedative effect and lack EPS which is due to preferential effect on limbic in comparison with striatal tissue (extrapyramidal). • Its hydrophilic properties causes its poor oralabsorption, limited penetration into CNS and resulting low potency.

20. b) Remoxipride • It is orally well absorbed and has nearly the same potency as haloperidol but with fewer incidences of extrapyramidal and autonomic side effects. • It causes aplastic anemia, that may limit its use as antipsychotic drug. Metoclopramide S-(-)-Sulpiride S-(-)-Remoxipride

21. IV- Benzazepine Derivatives. • Clozapine (Clozaril) It is dibenzazepine antipsychotic with minimal EPS and alleviates negative symptoms of schizophrenia. • Its serious drawback is the fatal agranulocytosis. • It has low affinity for dopamine D1 and D2 receptors in comparison to its affinity at adrenergic a1; and a2, H1, muscarinic M1 and serotonin 5-HT2A, receptors, thus, its special use may be through interactions with other receptors. 2) Loxapine (Loxitane) • 2-Chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][l,4]oxazepine. • It is typical neuroleptic with mainly antidopaminergic activity at D2- receptors. Loxpine (R=CH3) Amoxapine ( R=H)

22. 3) Amoxapine(Asendin) • Loxapine undergoes N-demethylation to form amoxapine which is used clinically as antidepressant • It binds to D2 receptors and inhibits the norepinephrine neurotransporter to block norepinephrine re-uptake, a correlate of antidepressant activity. V- Indole derivatives and isosteres • Their antipsychotic activity is based on that serotonin (5-hydroxytryptamine) is involved in schizophrenia; therefore certain indolamine analogs might be useful neuroleptic agents • The chemical structure of some neuroleptic (droperidol and pimozide) are indole or its isostere

23. Molindone (Moban): 3-Ethyl-6,7-dihydro-2-methyl-5- (morpholinomethyl)indole-4(5H)one • It is a tetrahydroindolone derivative which used in acute and chronic schizophrenia. • It is less potent than haloperidol in blocking D2 receptors, however, it can produce EPS. • It is rapidly absorbed and metabolized when given orally ( last more than 24 hours.) Sertindole (Serdolect). • It is indole and acts as serotonin 5-HT2 receptor antagonist with no affinity for dopaminergic D2 receptors.

24. Advantages: • It is as effective as haloperidol in treatment of acute and chronic schizophrenia, • much lower incidence of EPS. • It is non-sedating and long lasting (several days). VI- Benzisoxazoles • The proposal that combination D2/5-HT2 antagonists may produce atypical antipsychotic effects. Risperidone It is 5-HT2/D2 antagonist. 3-(4-piperidinyl)-1,2-benzisoxazole

25. The anti-serotonergic effects of risperidone are proposed to un-inhibit dopaminergic neurotransmission in the striatum and cortex, reducing the severity of D2 antagonist-induced EPS and alleviating negative symptoms of schizophrenia, while maintaining a blockade of limbic system D2 receptors. It is well absorbed orally. VII- Antimanic agents • Lithium salts are used as antimanic agents. • Lithium chloride is not used because it is hygroscopic and more irritant than carbonate or citrate salts to the GIT.

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